Translational Bioinformatics and Systems Biology Methods for Personalized Medicine

Translational Bioinformatics and Systems Biology Methods for Personalized Medicine

Qing Yan

Table of Contents

Cover image

Title page

Copyright

Preface

Part I. Concepts and Basic Tools

Chapter One. Introduction: Translational Bioinformatics and Personalized Medicine

1.1. Current Challenges in Biomedicine

1.2. Translational Bioinformatics as the Vehicle Toward Personalized Medicine

1.3. The Goals and Missions

Chapter Two. Systems and Dynamical Medicine: The Roles of Translational Bioinformatics

2.1. The Integration of Pharmacogenomics and Systems Biology

2.2. Translational Bioinformatics, Personalized and Systems Medicine

2.3. The Basic Concepts of the Complex Whole Body System

2.4. Systems and Dynamical Medicine With P4 Features

Chapter Three. Translational Bioinformatics Support for Omics Studies: Methods and Resources

3.1. Introduction

3.2. Bioinformatics Methods and Resources for Omics Studies

3.3. Bioinformatics Methods and Resources for Epigenomics and MicroRNA Studies

3.4. Bioinformatics Support for the Studies of Disease Phenotypes and Drug Responses

3.5. Bioinformatics Support for the Spatiotemporal Studies Toward Dynamical Medicine

3.6. Conclusion

Chapter Four. Data Integration, Data Mining, and Decision Support in Biomedical Informatics

4.1. Introduction: Data and Workflow Integration in Translational Bioinformatics

4.2. Approaches of Data and Workflow Integration

4.3. Data Mining and Knowledge Discovery in Translational Bioinformatics

4.4. Conclusion: Decision Support in Translational Bioinformatics

Part II. Applications in Basic Sciences

Chapter Five. Applying Translational Bioinformatics for Biomarker Discovery

5.1. Introduction: Concepts and Approaches

5.2. Challenges and Translational Bioinformatics Methods for Biomarker Discovery

5.3. Finding Robust Biomarkers for Systems and Dynamical Medicine

Chapter Six. Biomarkers From Systems Biology and Omics Studies: Applications and Examples

6.1. Proteomic and Metabolomic Pathways and Biomarkers

6.2. Pathways as Potential Biomarkers: Examples

6.3. Potential microRNA Biomarkers and Examples

6.4. Dynamical Circadian Biomarkers and Chronotherapy

Chapter Seven. Understanding Dynamical Diseases: Translational Bioinformatics Approaches

7.1. Spatial Complexity in Systems Biology

7.2. Temporal Complexity in Systems Biology

7.3. Profiling of Dynamical Diseases for Systems and Dynamical Medicine

7.4. Translational Bioinformatics Methods for Studying Dynamical Diseases

Part III. Applications in Clinical and Translational Sciences

Chapter Eight. Translational Bioinformatics Methods for Drug Discovery and Development

8.1. Challenges in Drug Discovery and Potential Solutions From Profiling Interactomes

8.2. The Translational Side and the Bioinformatics Side

8.3. Translational Bioinformatics Resources for Drug Discovery and Development

8.4. Translational Bioinformatics Methods for Drug Discovery and Development

8.5. Conclusion: Systems-Based Models and Decision Support for Drug Discovery

Chapter Nine. Translational Bioinformatics and Systems Biology for Understanding Inflammation

9.1. Introduction: Systems Biology, Translational Bioinformatics, and Inflammation

9.2. The Microbiota–Gut–Brain Axis and Systemic Inflammation

9.3. Translational Bioinformatics Methods for the Studies of Inflammation

9.4. Identifying Systems-Based Biomarkers for Inflammation: Examples

Chapter Ten. Cardiovascular Diseases and Diabetes: Translational Bioinformatics and Systems Biology Methods

10.1. Translational Bioinformatics Methods for Studies in Cardiovascular Diseases

10.2. Lipidomics, Computational Systems Biology, and Drug Repositioning

10.3. Nutritional Systems Biology, Biomarkers, and Type 2 Diabetes

10.4. Finding Systems-Based Biomarkers for Cardiovascular Diseases: Examples

10.5. Finding Systems-Based Dynamical Biomarkers for Diabetes: Examples

Chapter Eleven. Translational Bioinformatics and Systems Biology for Cancer Precision Medicine

11.1. Introduction: Systems Biology, Cancer Precision Medicine, and Immunotherapy

11.2. Translational Bioinformatics Resources for Cancer Studies

11.3. Translational Bioinformatics Methods for Cancer Studies

11.4. Identifying Potential Systems-Based Biomarkers for Cancers

Chapter Twelve. Aging and Age-Associated Diseases: Translational Bioinformatics and Systems Biology Methods

12.1. Introduction: Challenges and Opportunities in Aging Studies

12.2. Resources and Methods in Translational Bioinformatics for Aging Studies

12.3. Comprehensive Omics Profiling for Neurodegenerative Diseases

12.4. Finding Potential Systems-Based Biomarkers for Aging and Associated Diseases

Index

Copyright

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Preface

The challenges that healthcare and pharmaceutical industries are facing demand improvements in various aspects, from scientific research to clinical practice. To solve these problems and improve the quality of care, it is urgent to translate the scientific findings from biomedicine into better clinical procedures and results. Because information and knowledge are the major contents in such translational process, novel bioinformatics methodologies such as data integration and knowledge discovery across various domains become critical. As an interdisciplinary field itself, translational bioinformatics provides a special opportunity for overcoming the barriers and obstacles among knowledge domains and clinical branches, and between basic science and clinical bedside practice.

This book provides an introduction and overview of translational bioinformatics and systems biology approaches in support of the development of personalized, systems, and dynamical medicine. The first part of the book introduces and discusses some basic concepts and tools. The second part describes the resources, methods, and applications for finding effective biomarkers and understanding disease complexity. The third part of the book focuses on the translational bioinformatics and systems biology methodologies in drug discovery and clinical applications, including inflammation, cardiovascular diseases (CVDs), cancer, aging, and age-associated diseases.

Specifically, the applications of systems biology and translational bioinformatics may contribute to the development of systems and dynamical medicine with the predictive, preventive, personalized, and participatory (P4) features (see Chapter 2). For the practice of translational bioinformatics, one of the first steps would be to get the necessary resources. Various tools are available for supporting omics studies in systems biology (see Chapter 3). Some of the important steps are data integration, data standardization, data mining, knowledge discovery, and decision support (see Chapter 4).

An essential component of personalized medicine is useful biomarkers for quantified and more precise diagnosis and prognosis (see Chapter 5). Proteomics and metabolomics studies are essential in systems biology. The analyses of data from these studies may promote the accuracy, sensitivity, and throughput for biomarker identification because the proteome represents the functional actors in a cell (see Chapter 6). The dynamical properties in the diseases need to be addressed with the shifting targets at various levels during various stages for better therapies (see Chapter 7).

Such approaches would enable the detection and prediction of disease progression and drug responses for improving the safety, utilization, and effects among new and existing drugs, such as the strategies in drug repositioning and drug combinations (see Chapter 8). Translational bioinformatics methods can help identify systems-based biomarkers to address the complexity in the inflammation-associated disease classifiers and patient stratifications (see Chapter 9). Computational systems biology strategies have been proven useful for drug repositioning in the treatment of CVDs (see Chapter 10). The identification of systems-based and dynamical biomarkers representing the evolving processes in cancer development may help support cancer precision medicine (see Chapter 11). Translational bioinformatics may also enhance the understanding in the systems biology of aging with the simulation of the dynamics of biological systems in the aging processes (see Chapter 12).

The integrative and multidisciplinary approaches in the book may be helpful for bridging the gaps among different knowledge domains. This book intends to provide a state-of-the-art and integrative view. By covering topics from basic concepts to novel methodologies, this book can be used by biomedical students, scientific experts, and health professionals at all levels.

Users may include those who are interested in genetics, genomics, proteomics, bioinformatics, systems biology, bioengineering, biochemistry, molecular biology, cell biology, physiology, pathology, microbiology, pharmacology, toxicology, neuroscience, immunology, drug discovery and development, and various branches in clinical medicine.

I would like to thank the editors for their support in this exciting project.

Qing Yan, MD, PhD

Part I

Concepts and Basic Tools

Outline

Chapter One. Introduction: Translational Bioinformatics and Personalized Medicine

Chapter Two. Systems and Dynamical Medicine: The Roles of Translational Bioinformatics

Chapter Three. Translational Bioinformatics Support for Omics Studies: Methods and Resources

Chapter Four. Data Integration, Data Mining, and Decision Support in Biomedical Informatics

Chapter One

Introduction

Translational Bioinformatics and Personalized Medicine

Abstract

The challenges that healthcare and pharmaceutical industries are facing demand improvements in various aspects, from scientific research to clinical practice. To solve these problems and improve the quality of care, it is urgent to translate the scientific findings from biomedicine into better clinical procedures and results. Because information and knowledge are the major contents in such translational process, novel bioinformatics methodologies such as data integration and knowledge discovery across various domains become critical. As an interdisciplinary field itself, translational bioinformatics provides a special opportunity for overcoming the barriers and obstacles among knowledge domains and clinical branches, and between basic science and clinical bedside practices. The novel translational bioinformatics methodologies would allow for the identification of improved drug targets, drug development pipelines, and reduced adverse reactions, with better quality of care. An important task of translational bioinformatics for supporting personalized medicine is to construct predictive models for disease progression and treatment responses.

Keywords

Data; Diseases; Information; Integration; Knowledge; Personalized medicine; Pharmacogenomics; Systems biology; Systems medicine; Translational bioinformatics

1.1. Current Challenges in Biomedicine

The tremendous challenges that healthcare and the pharmaceutical industries are facing demand improvements in various aspects, from scientific research to clinical practice. A few examples of these challenges are the rapidly rising costs of clinical care and the growing expenses in drug research and development.

On the other hand, fewer new drugs are being approved by the US Food and Drug Administration, with an increasing rate of high-profile drug withdrawals (Caskey, 2007). In the meantime, the high incidence of adverse drug reactions (ADRs) has become so severe that ADRs are one of the leading causes of morbidity and mortality although many of them are preventable (Ross et al., 2007; Yan, 2011).

Improvements in both scientific and technical aspects are needed to overcome the obstacles and meet the challenges. Considering the scientific aspect, the reductionist drug discovery methods featuring one-size-fits-all and single target have been found to contribute to various ADRs (Yan, 2011). These conventional approaches ignore differences between individuals and the interrelationships among drugs, humans, and the environment at various system levels.

In the technological aspect, the gaps in multidisciplinary communications and collaborations have made it difficult to translate the scientific discoveries into more efficient and effective clinical outcomes. In addition, the inadequacies of standardization in the physician ordering systems have led to numerous clinical mistakes and adverse events (Yan, 2010). Another computational challenge related to systems medicine is the integration and analysis of voluminous datasets for identifying patient and disease subtypes (Saqi et al., 2016).

In the scientific aspect, an important factor behind the challenges and obstacles is the conventional healthcare model that is reductionism based and disease centered (Ray, 2004). Such models originating from the late 19th century emphasize the linear bonds between clinical symptoms and pathological detections regarding diseases, diagnosis, and therapeutic approaches (Loscalzo and Barabasi, 2011). On the basis of the reductionist philosophies rather than the complex and nonlinear systems in reality, these simple models are no longer applicable with the novel discoveries in functional genomics and systems biology.

Specifically, approaches such as high-throughput (HTP) technologies and understandings in proteomics, metabolomics, epigenomics, and interactomics have revealed the interrelationships among the components at different system levels (see Chapter 3). Such novel findings request revolutionary improvements in healthcare practice. The novel direction in response to these demands should be heading toward the integrative paradigm that is human centered and individual based (Yan, 2008a).

This change of gear is not possible without scientific and technological support. However, the current situation is that many of the scientific discoveries just stay in the scientific laboratories but cannot benefic clinical practice (Yan, 2010). Although there have been significant scientific advancements, thorough understandings, accurate diagnosis, and effective therapies are still needed for most of the complex diseases.

To solve these problems and improve the quality of care, it is urgent not only to improve but also to translate the scientific findings in biomedicine into better clinical procedures and results (Yan, 2011). The term translation here emphasizes the bidirectional flow of information and knowledge between the bench side of the basic scientific research and the bedside of clinical performance.

Because information and knowledge are the major contents in such translational process, novel bioinformatics methodologies such as data management and knowledge discovery across various domains become critical (see Chapter 4). These approaches would also enable better strategies for drug discovery, development, and administration with lower costs and higher efficiencies.

By addressing the challenges in personalized medicine, translational bioinformatics provides the opportunities and detailed strategies not only for the management and analyses of biomedical data but also for the promotion of proactive and participatory health (Overby and Tarczy-Hornoch, 2013). Translational bioinformatics can serve as the pivotal vehicle to integrate various emerging disciplines including pharmacogenomics and systems biology toward the advancement of personalized, preventive, predictive, and participatory (P4) medicine (Hood and Flores, 2012; also see Chapter 2). This chapter will provide an introduction and extensive discussion of this vehicle.

1.2. Translational Bioinformatics as the Vehicle Toward Personalized Medicine

1.2.1. The Demand

The advancements in the emerging fields of pharmacogenomics and systems biology may contribute to the development of personalized and systems medicine (Yan, 2008b). As discussed above, this objective is difficult to accomplish without the translational processes bringing the scientific breakthroughs into clinical practices and results. Such translational processes rely on bioinformatics methodologies as the critical vehicles.

For example, studies in systems biology using technologies such as HTP have generated tremendous